The invention relates to a device for the delayed release of an active substance, especially a veterinary active substance.
In the past fifteen years, much research has been carried out in veterinary pharmacy in order to optimize the release of medicinal products in domestic rearing animals or pets.
One of the main axes of research is directed towards developing anthelmintic compounds intended for the treatment of the verminoses of ruminants (bovines, goats, etc.).
As regards the oral route, the most common formulations involve medicinal premixes or granules containing anthelmintic agents. More sophisticated formulations have also been designed for the oral route. These allow release of the active principle over a longer period of time and thereby avoid the need to regularly retreat the animals and to seek them out in the pasture in order to administer treatment. These devices with sustained release of active principle (also known as intraruminal diffusers or boli) allow release of the active principle by diffusion across a matrix excipient by erosion of one of the components constituting the device, by the action of an electronic system which allows programmed release over time, or alternatively by osmotic pressure.
These devices are maintained in the rumen of the ruminants either by means of the density of the device or its specific geometry which prevents regurgitation of the bolus during rumination.
However, on account of the constraints imposed by the size of the device which needs to be administered and the daily amount of product which needs to be released in order to obtain a pharmacological effect, one of the major problems lies in the fact that the active principle is released over an insufficient period, 140-150 days at most, with the amount of active principle released not increasing during the season in pasture, or even decreasing over time.
In addition, another drawback is that the active principle is essentially released during the first months in pasture, when the fields contain a relatively low number of worms and eggs, while the digestive tract and the lungs of the animals contain few worms or larvae at the start of the season in pasture. As a result, the animals generally show no infestation or any clinical signs due to verminoses during this period.
Furthermore, the immediate release of the active principle when the animals are placed in pasture at an early stage compromises the release of this active principle at a stage at which it would be necessary, i.e. in July and August.
Early release of the active principle also has the drawback of avoiding contact between the host and the infesting agent at a stage when this contact would allow the ruminant to acquire immune protection against these parasites.
A need thus exists for a device which would, on the one hand, allow a lag phase after ingestion of the device by the animal, before any release of active principle at the moment when the animals are placed in pasture, and which would, on the other hand, ensure a release of an active agent, in particular an anthelmintic agent, continuously or preferably in waves, in an amount increasing as a function of time during the months of July and August.
So as to satisfy such a need, the subject of the invention is a device for distributing an active substance, this device being intended to be used in a biological medium, in particular the rumen of an animal, comprising:
a leakproof container intended to contain the said substance, the said container comprising at least one opening;
a means for temporary closure of the opening of the said container, the said closure means being held closed by at least one biodegradable component, such that, after the said component has biodegraded, the closure means completely frees the said opening.
In a first embodiment, the container is a flexible leakproof sachet or a leakproof sachet with a certain amount of rigidity and which can be rolled up and unrolled. Any nonbiodegradable leakproof material may be suitable. Mention may be made of a nonbiodegradable polymer, in particular a polypropylene, polyester, polyvinyl, etc.
The closure means advantageously includes a member formed of two components which are applied one on top of the other.
These two components can be held together at each of their ends by the biodegradable component. They can also be linked together by a portion forming a hinge and held together at only one end by the said biodegradable component.
These two components preferably comprise complementary longitudinal grooves on their inner face, such that, when the two components are applied one on top of the other, the grooves interlock and ensure the total leaktightness of the closure means.
The closure means advantageously comprises a clip, which is normally open, and is held closed by means of the biodegradable component, the said clip preferably having arms comprising interlocking grooves.
In a second embodiment, the container is formed of a rigid cup of cylindrical shape, closed at one of its ends and open at its other end, and the means for temporary closure of the said open end comprises a disk pierced with a central orifice, a stopper whose shape matches that of this central orifice and which is held on the said central orifice by the biodegradable component supported by a ring, and by a collar intended to be fixed onto the cup in order to keep the disk and the ring applied against the open end of the said cup.
In a third embodiment, the receptacle is formed of a cylinder comprising a ballasting component at one of its ends and a stopper provided with perforations at these [sic] other end, and this cylinder comprises several superposed compartments each containing an active substance, the said compartments being interconnected and each being closed off by the said temporary closure means.
Each compartment is formed of a cartridge provided with outer screw threading at one of its ends and inner screw threading at its other end.
In this embodiment, the means for temporary closure of each compartment comprises a disk pierced with a central orifice, a stopper whose shape matches that of this central orifice and which is held on the said central orifice by the biodegradable component supported by a ring applied onto the said disk by the cartridge of the adjacent compartment.
In a fourth embodiment, the receptacle is formed of an envelope of elongate shape made of leakproof material which is not biologically degradable, the receptacle comprising an opening at at least one of its ends and containing a matrix formed of a resin in which particles of a high-density material and particles of the said active substance are distributed, the said opening being held closed by the said biodegradable component.
The envelope comprises an opening at each of its ends and the matrix comprises a passage extending over the entire length of the said matrix and aligned in the axis of the said openings, each of these openings being closed off by a stopper made of nonbiodegradable material and the said stoppers being linked together by the said biodegradable component.
In a fifth embodiment, the receptacle is formed of a cylindrical container comprising two half-shells linked together at one of their ends by a portion forming a hinge and at its other end by the said biodegradable component in order to keep the container temporarily closed.
The half-shells are advantageously designed to contain a delayed-release form of an active principle of the type comprising a matrix in which an active principle is dispersed and a central hollow being provided in the said matrix in order to allow a graded release of the active principle based on the differences in migration path of the active principle from the matrix to the central hollow.
The biodegradable component advantageously consists of a thread or a strip made of a biologically degradable polymer.
Any biodegradable polymer material is suitable. Mention may be made of polyglycolic acid (PGA), polylactic acid (PLA) or a copolymer of polyglycolic acid and of polylactic acid (PLGA), poly(xcex5-caprolactone) (PCL), poly(p-dioxanone), polyanhydrides, polyorthoesters, etc.
In one preferred embodiment of the invention, the biodegradable component consists of a surgical suture thread, in particular a single-filament or braided surgical suture thread.
Threads of this type which may be suitable are, in particular, polyamides, such as those described in U.S. Pat. No. 5,068,220, polyglycolic acid polymers, for example the one sold under the brand name Vicryl(copyright); a copolymer of glycolic acid and of lactic acid, for example the one sold under the brand name Dexon(copyright); a copolymer of trimethyl carbonate and of glycolic acid, for example the one sold under the brand name Maxon(copyright); a poly(p-dioxanone), for example the one sold under the brand name PDS II(copyright), an xcex5-caprolactone/glycolic acid block copolymer, for example the one sold under the brand name Monocryl(copyright). The diameter of the thread or strip is variable and depends on the size of the device, the nature of the material used and the time after which its degradation is desired.
A person skilled in the art is capable of determining the thickness of this thread or strip, by means of routine calculations. Preferred suture thread sizes correspond to the numbers: 0, 1/0 and 2/0.
Closure of the strip or suture thread is ensured by maintaining tension on the ends of the strip or thread, by any suitable means, in particular by means of a knot or any external device for holding together the free ends of the thread or strip, such as adhesive, wax, a non-degradable polymer, a circlip, etc.
A bioresorbable screw made of a material which is resorbed by hydrolysis, such as a high molecular weight polymer of polylactic acid or polycaprolactone type, is also advantageously used.
A screw of this type is used in maxillofacial surgery and is sold under the name Phusiline(copyright).
The biologically active substance advantageously consists of a medicinal product, in particular an anthelmintic agent, a growth promoter, etc., the device being intended in this case to be introduced into the stomach of a ruminant.
When the device is a flexible sachet, in particular, and when the suture thread has lost its mechanical properties, the release of the active substance can be facilitated by formulating the active principle in an effervescent pharmaceutical form or by adding an effervescent mixture with no pharmacological properties into the sachet along with the diffuser. In this case, the mixture can consist of citric acid and sodium bicarbonate, or other mixtures whose hydration produces a gas.
By dilating the flexible sachet, this gas facilitates the release of the active substance into the surrounding biological medium.
In order to avoid regurgitation phenomena, the device according to the invention, in particular in the form of the first embodiment of the invention, can be inserted in a bag which is provided with perforations or which allows easy diffusion of the active principle, or the sachet of the device will contain either a rolled-up sheet which, after unrolling, will prevent regurgitation of the device, or will be made more dense by the addition of a component for increasing the density.
Advantageously, the device then comprises a flexible or deformable sachet containing a support sheet in which an active principle is dispersed, the said support sheet being designed so as to be able to be arranged positively, by deformation, in a first rolled-up form and to take a second form in the rumen, the device being held in the rumen by virtue of this second form.
A subject of the invention is also a device as described for the first embodiment of the invention, comprising a flexible or deformable sachet containing a support sheet of the abovementioned type, the sachet and the support sheet being in a rolled-up form with the closure means located inside the roll, and the assembly being held in this rolled-up form by a positive deformation means which can be rapidly eliminated in the rumen.
The perforated sheet or sheet provided with perforations can also be rolled up around the device and the assembly included in a bag as described above.
Systems of this type in the form of a matrix capable of rolling up and unrolling once in the rumen of an animal are described in EP 334,516, U.S. Pat. No. 3,844,285 and EP 10,967.
The regurgitation phenomena can also be avoided by providing the device of the invention, in particular in the second, third and fourth embodiments of the invention, in an elongated cylindrical form provided with a ballasting component.
A subject of the invention is also a system for distributing one or more active substances, which is intended to be used in a biological medium, in particular the rumen of an animal, this system comprising at least two devices arranged one inside another, each container containing, optionally besides the said active substance, at least one other similar container, or each container being contiguous with the others.
In a first embodiment of the multi-container system of the invention, the system comprises a first outer device as described above in relation to the first embodiment of the invention, preferably containing an active substance and in turn comprising at least one other similar device containing a biologically active substance, this substance preferably being different from the one contained in the outer device or the device(s) arranged in the outer device. This system thus allows the release of biologically active substances of different nature, in particular of the substances which are incompatible in terms of chemical and/or physical stability or which are pharmacologically incompatible.
In a second embodiment of the multi-container system, the devices are organized in a nesting arrangement. In other words, the system comprises a first outer device containing, besides an active substance, a device of smaller size which contains, besides a second active substance, a third device smaller than the second device, and so on.
One or other of the systems described above can be designed so as to provide a sequential release as a function of the pharmacological, chemical and physical properties of several different active principles.
The active substances can be of different nature, or of the same nature and of different dosages. It is thus possible to provide a system of devices arranged one inside another in a nesting manner, in which the containers for the respective devices contain the same active substance, but at increasing doses, in going from the outermost system to the innermost system. In this manner, release of the biological substance will be obtained over time, such that, when this is an anthelmintic substance, the maximum dose will be released at a chosen moment, for example at the end of the season in pasture, or alternatively the release of active principles in different physical forms, for example a liquid active principle and another solid.
Nonlimiting examples of active principles with pharmacological activity which can be administered by means of a device and/or a system according to the invention are anthelmintic agents such as ivermectin, morantel tartrate, levamisole hydrochloride, oxfendazole, etc., trematicides, in particular rafoxanide, antibiotics and vaccines.